There are currently more than 60,000 chemicals introduced into the environment each year, most of which have never been evaluated for potential neurotoxicity. Recent examples of neurotoxic disease emphasize the need to detect, evaluate, and understand the impact of toxins on man's nervous system. To help address these needs, this experimental neuropathological praoject will expose rates chronically to 2,5-hexaandedione, a prototype agent producing dying-back axonal degeneration. The overal objective of this project is to help elucidate the cell body response to toxicant-induced axonal degeneration. Preliminary work (Sterman, Ann Neurol, in press) demonstrates, for the first time, a spectrum of cell body modifications. Selected groups of central and peripheral neurons will be studied morphologically to assess changes in the cell body (including dendrites and synaptic terminals), and to correlate these alterations with the status of axons emerging from the same cell bodies. This project has two major goals. First, because the neuronal cell body shows characteristic alterations during early disease (pilot studies), it may serve as a sensitive marker of neurotoxic potential in in vivo screening assays. Second, since nervous functioning is vitally dependent on intact cell body structure, including synapses and dendrites, it is critically important to understand alterations in these structures during intoxication and recovery. These has never been a systematic study focusing on cell body changes during toxin-induced axonal degeneration. Besides these immediate practical goals, this project is likely to help illuminate the pathogenesis of dying-back axonal degeneration, cell body-axon interactions, and address central questions in toxic neuropathies.